Genetic and environmental factors play an important role in the etiology of nephrolithiasis. This project will build on and extend our previous efforts (examining environmental risk factors for stone formation) by allowing us to study the risk of stone formation associated with specific genes and gene-environment interactions. We will take advantage of previously collected data in three large cohort studies: Nurses' Health Study I (n=121,000 women), Nurses' Health Study II (n=116,000 women), and Health Professionals Follow-up Study (n=51,000 men). Over a period of 14 to 24 years, information has been collected prospectively on important exposures including diet, family history, body size measures, past medical history, and medications. We have confirmed over 1600 incident cases of kidney stones in each cohort and are in the process of identifying additional incident cases (DK59583, PI Curhan). Further, we have collected 24-hour urine samples from over 3000 cases and controls and will collect another ~1000 over the next three years; the majority of participants have performed two collections. Using a nested case-control design, the primary objective of this project is to examine the role of specific genetic risk factors for incident nephrolithiasis. The secondary objective is to explore interactions between the genetic factors, dietary factors (particularly calcium intake) and risk of incident stone formation. The final objective is to examine the impact of these genetic factors and gene-environment interactions on 24-hour urinary excretion of relevant lithogenic factors. This project will interact with each of the other projects and cores. Polymorphisms and haplotypes from Projects 1-3, as well as additional gene candidates identified from the Genetics Core, will greatly enhance the scope and depth of this study, and will increase the likelihood of identifying clinically meaningful associations between genetic factors/diet, the urinary supersaturation of calcium salts/and kidney stone formation. A P-value of 0.001 will be used as the threshold for statistical significance to reduce the likelihood of false-positive associations. These findings should provide insight into new approaches for prevention of stone formation.